Insulin is secreted from β cells of pancreatic Langerhans islet, and lowers the blood sugar level by predominantly acting on muscle, liver and fat to allow sugar in blood to be incorporated into the cell, stored therein, and consumed. Diabetes is caused by insufficient function of the insulin, and there are two types of patients, i.e., type 1 having disorder in production and/or secretion of insulin, and type 2 having difficulty in acceleration of sugar metabolism by insulin. In either patient, blood sugar level is higher than that in healthy people. However, blood insulin is absolutely deficient in the type 1, while insulin resistance is developed in which the incorporation and consumption of blood sugar is not accelerated irrespective of the presence of insulin in the type 2. Type 2 diabetes is the so-called life-style related disease, which results from overfeeding, lack of exercise, stress and the like in addition to hereditary predisposition. In these days, the type 2 diabetic patients have increased rapidly as the caloric intake is elevated in advanced nations, and in Japan, such patients account for 95% of the diabetic patients. Thus, therapeutic drugs for diabetes should not only be simple hypoglycemic agents, but the necessity of studies of therapy targeted to type 2 diabetes has increased in which glucose metabolism is accelerated through the improvement of insulin resistance.
Currently, for the therapy of type 1 diabetic patients, an insulin injection formulation is prescribed. On the other hand, examples of known hypoglycemic agents prescribed for type 2 diabetic patients include: sulfonylurea hypoglycemic agents (SU agents) which act on pancreatic β cells to accelerate secretion of insulin; biguanide hypoglycemic agents having activity to increase utilization of sugar by anaerobic glycolytic activity, to suppress gluconeogenesis, and to suppress intestinal absorption of sugar; as well as α-glucosidase inhibitors which retard digestion and absorption of carbohydrates, in addition to insulin injection formulations. Although these agents indirectly improve insulin resistance, thiazolidine derivatives have been used as agents which directly improve insulin resistance, in recent years. Its activity is to incorporate glucose into the cells, and to accelerate utilization of the glucose within the cells. The thiazolidine derivative has been demonstrated to act as an agonist of peroxisome proliferator activated receptor gamma (PPARγ) (nonpatent document 1). However, the thiazolidine derivative has been known to exhibit not only the improving effect on insulin resistance but a side effect to cause edema (nonpatent documents 2–3). Since the induction of edema is a serious side effect which results in cardiac hypertrophy, for the purpose of the improvement of insulin resistance, useful target molecules for development of new drugs which can be an alternative to PPARγ have been desired.
Signal of the insulin function is transduced into a cell via an insulin receptor on the cell membrane. In the action pathway of insulin, there are two pathways, i.e., first and second pathways (nonpatent document 4). In the first pathway, the signal is sequentially transduced from the activated insulin receptor via IRS-1 and IRS-2, PI3 kinase, PDK1 to Akt1 (PKBα) or Akt2 (PKBβ), or PKCλ or PKCζ. As a result, incorporation of sugar from outside of the cell is accelerated by translocating a glucose transporter GLUT4, which is present within a cell, onto the cell membrane (nonpatent document 5). On the other hand, in the second pathway, the signal is sequentially transduced from the insulin receptor via c-Cbl and CAP to CrK II, C3G and TC10, and consequently, the incorporation of sugar by GLUT4 is accelerated (nonpatent document 6). However, details of the insulin signal transduction pathway are still unclear in part, and particularly, it is not clear which mechanism is finally involved in these signals to accelerate the cellular incorporation of sugar via the glucose transporter.
CAP is an adaptor protein which exists in the second pathway of the insulin signaling, and is highly expressed in liver, skeletal muscle, kidney and heart which are insulin sensitive tissues (nonpatent document 7). Furthermore, the expression of CAP has been known to be enhanced by a thiazolidine derivative which is a PPARγ agonist (nonpatent document 8). CAP binds to c-Cbl via an SH3 domain at its C-terminal side. The CAP/c-Cbl complex responds to the insulin signal, thereby activating TC10 via a CrkII-C3G complex to accelerate the translocation of the glucose transporter GLUT4 to the cell membrane. It was reported that although CAP having deficiency of SH3 which is a binding domain to c-Cbl (CAP ΔSH3) does not affect the PI3 kinase activity, it inhibits cellular incorporation of sugar (nonpatent document 9). From these findings, it is believed that CAP is a signal mediating factor which acts in incorporation of sugar into cells depending on the binding to c-Cbl, and that the inhibition of its function may result in insulin resistance through partial blocking of insulin signal transduction, thereby causing type 2 diabetic pathologic conditions.
Patent Document 1
    Pamphlet of International Publication No. 01/75067Patent Document 2    Specification of U.S. patent Publication No. 2002/0119919Patent Document 3    Pamphlet of International Publication No. 00/58473Nonpatent Document 1    The Journal of Biological Chemistry, (USA), 1995, Vol. 270, pp. 12953–12956Nonpatent Document 2    Diabetes Frontier, (USA), 1999, Vol. 10, pp. 811–818Nonpatent Document 3    Diabetes Frontier, (USA), 1999, Vol. 10, pp. 819–824Nonpatent Document 4    The Journal of Clinical Investigation, (USA), 2000, Vol. 106, No. 2, pp. 165–169Nonpatent Document 5    The Journal of Biological Chemistry, (USA), 1999, Vol. 274, No. 4, pp. 1865–1868Nonpatent Document 6    Nature, (United Kingdom), 2001, Vol. 410, No. 6831, pp. 944–948Nonpatent Document 7    Molecular and Cellular Biology, (USA), 1998, Vol. 18, No. 2, pp. 872–879Nonpatent Document 8    The Journal of Biological Chemistry, (USA), 2000, Vol. 275, No. 13, pp. 9131–9135Nonpatent Document 9    The Journal of Biological Chemistry, (USA), 2001, Vol. 276, No. 9, pp. 6065–6068Nonpatent Document 10    Molecular and Cellular Biology, (USA), 2002, Vol. 22, No. 11, pp. 3599–3609